Periodic Reporting for period 4 - SPLICECODE (Alternative Splicing Codes for Synaptic Specificity)
Reporting period: 2021-04-01 to 2021-09-30
Brain disorders represent a major challenge for today's societies. Despite intensive research efforts, therapeutic interventions for most psychiatric and aging-related disorders have been of moderate success. Obtaining better insight into the normal development of the nervous system - in particular the underpinnings of funcitonal properties of specific neuronal cell types - might enable more targeted interventions in the future. The goal of this project is testing the hypothesis that alternative splicing is a central mechanism for the amplification of molecular diversity in neuronal cells and that it controls critical aspects of synaptic specificity. To this end, we proposed to implement novel mass-spectrometry and RNA sequencing methods to define molecular diversity of neuronal gene families in mouse neurons. Moreover, we sought to unravel the logic of neuronal receptor repertoires across cell populations and test the importance of cell type-specific alternative splicing programs for synapse specification.
Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far
We adopted and advanced technologies for the exploration of neuronal transcript isoforms in the mammalian nervous system. We demonstrated the function of regulators of RNA splicing as well as the control of synaptic properties by RNA splicecodes. We further pioneered proteome-level investigations providing for the first time direct evidence how particular splice variants are selectively addressed to specific neuronal synapses in the mouse brain. This work was published in several peer-reviewed manuscripts and presented in form of posters and oral presentations to the scientific community and the general public.
Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)
Our work provides the first example for a highly selective action of a neuronal RNA-binding protein that controls synapse specification. This demonstrates that RNA alternative splicing does not just "fine-tune" cellular functions but has instructive roles in specifying neuronal properties. By Performing genome-wide assessment of neuronal cell type-specific alternative splicing we uncovered extensive cell type-specific transcript isoform repertoires in genetically-defined neuron populations. This work demonstrated for the first time the logic of alternative splicing programs across major neuron classes. Finally, we developed a web-platform for public access to data on cell type-specific alternative transcript regulation in the nervous system. This represents a major resource of high-quality data for the scientific community. The insights gained in this project spurred efforts to develop novel therapeutics for neurological and neurodevelopmental disorders.